Named after the Titans — a group of powerful Ancient Greek gods — the element titanium is known for its strength and resistance to corrosion. Titanium and titanium alloys are used in a wide variety of applications, from the mundane, such as in house paint, to more exotic uses, like in propellers and rotor blades, and in high-speed spy planes.

Titanium’s strength, as well as its excellent biocompatibility, is also integral to a device that is changing the lives of children with a debilitating rare disease, offering hope of drastically improved outcomes.

Left untreated, TIS can be devastating. As children with TIS grow, the condition causes the chest become deformed, and children with TIS are often born with scoliosis, or curvature of the spine. TIS can lead to death due to respiratory insufficiency. However, since Dr. Campbell implanted the first VEPTR in 1989, the device — which as its name implies can be expanded as the child grows — has proven to be a lifesaver.

Indeed, a recent Journal of Pediatric Orthopaedicsstudy showed the VEPTR gives children with Jeune syndrome, a condition related to TIS, a chance not just to survive, but also to grow and thrive. The study, which Dr. Campbell led alongside colleagues from Texas, found VEPTR treatment improved Jeune syndrome patients’ survival dramatically compared to natural history untreated.

A very rare disease, Jeune syndrome — or asphyxiating thoracic dystrophy — affects approximately 1 in 100,000 infants each year. A multisystem, congenital disorder, Jeune syndrome is characterized by distinctive narrow, bell-shaped chest, shortened limbs, and at times polydactylism. Those born with Jeune syndrome experience breathing problems, and can develop renal, hepatic, and cardiac issues. The chest hypoplasia caused by Jeune syndrome results in severe TIS.

In the Journal of Pediatric Orthopaedics paper, Dr. Campbell and colleagues describe the use of VEPTR to treat 24 patients with Jeune syndrome, at an average of 23 months of age. Of those, two were lost to follow-up, and 17 had a minimum of two years of follow-up examinations. In all, the survival rate of the 22 patients was 68 percent, with less dependence on ventilators.

“This study is, to our knowledge, the largest of the surgical treatment of Jeune syndrome with long-term follow-up, and we are especially excited that the survival rate after surgery was nearly 70 percent, compared to a 70 to 80 percent mortality rate for untreated Jeune syndrome patients, and most were weaned off their ventilators,” said Dr. Campbell.

The procedure “flips” the survival curve,” the researchers note, “and greatly improves quality of life by diminishing the need for oxygen support, CPAP, and ventilator support for these children.”

In addition to the dramatic about-face in survival rate, the researchers also noted VEPTR treatment increased total chest diameter, thoracic spine height, and lumbar spine height. Assisted ventilation rating scores— which Dr. Campbell and his team used to measure pulmonary function — improved in many of the patients, with several who had been entirely dependent on a ventilator before surgery weaned off after treatment.

And Dr. Campbell’s Journal of Pediatric Orthopaedics study is hardly the only promising research that makes use of the VEPTR. A quick search of PubMed reveals a host of VEPTR-related papers, including 27 since the beginning of 2013.

“New advances in surgery occur frequently, but only the test of time can show their true worth at long term follow-up,” Dr. Campbell added. “The VEPTR techniques appear to be living up to their promise.”

At 3 foot 8 inches, 66 pounds, Leta Moseley is a tiny teenager with a big personality. Seventeen years ago, her family embarked on a medical odyssey in search of a diagnosis for Leta, who has cognitive disabilities, speaks only a few words, and has lung disease and heart irregularities. A bad virus can land her in The Children’s Hospital of Philadelphia for several weeks, at times on a ventilator for breathing support. Yet when she is healthy, Leta can take over a dance floor with her swirls and smiles.

CHOP medical geneticist and researcher Ian Krantz, MD, has been a tireless detective in his efforts to find out what genetic anomaly could be behind Leta’s constellation of symptoms. She had many characteristics in common with his patients with the rare multi-system disorder Cornelia de Lange Syndrome that Dr. Krantz has long studied. But her clinical features weren’t a perfect fit for this diagnosis, and genetic testing for Cornelia de Lange syndrome was negative.

Over the past 10 years, Dr. Krantz and his team identified two other unrelated children (who live less than 200 miles away) with clinical features that seemed to match Leta’s. Using samples from all three children, his research team made the groundbreaking discovery “back home” in the genetics lab at CHOP. With the help of a breakthrough in sophisticated gene-sequencing technology that became available two years ago, they analyzed the protein-coding portions of DNA (exomes) and identified mutations in the AFF4 gene in Leta and the other two children. In genetic research, this is the equivalent of finding a needle in a haystack.

“This is a great example of how families and their doctors work together over many years to find answers and advance both science and the care of their children,” Dr. Krantz said. “Although it has been a long road to get to this point, it is really just the beginning, and we still need to work closely with the families to fully understand the significance of this discovery and how best to use this information to take better care of Leta and other children with this diagnosis.”

After years of mystery and misdiagnoses, Leta’s family finally has a name for her disorder — a new diagnosis called CHOPS syndrome. The acronym stands for the group of symptoms seen in the three affected children: Cognitive impairment and coarse facial features, Heart defects, Obesity, Pulmonary involvement, Short stature and skeletal dysplasia (abnormal bone development).

As this novel finding is disseminated in a Nature Genetics report, Dr. Krantz expects that CHOPS syndrome may be the answer for other parents around the world who have been on a hunt for their child’s complex, undiagnosed genetic disorder. They may find reassurance that CHOPS syndrome is a de novo condition — which means that it resulted from a new mutation arising in a single egg or sperm that went on to form the affected child but is not present in the patient’s parents — so it is unlikely to recur in any subsequent children.

“Ending the ‘diagnostic odyssey’ for families has a profound psychological effect, allowing for closure and an understanding of how all of these myriad clinical differences in their child are linked to a single underlying cause,” Dr. Krantz said.

“It also ends a very expensive search for an answer often with many unnecessary diagnostic tests and blood draws,” he continued. “It allows us to find other children and adults with the same condition that in turn gives us a better understanding of the clinical issues and best options for management and to provide some idea of prognosis for families. We can more effectively counsel families about recurrence risk for themselves and family members. Most importantly, understanding the underlying molecular basis for the clinicalfindings in their children is the first step towards identifying targeted therapeutics in the future.”

In the below interview, Leta’s mom, Lainey Moseley, described her family’s steadfast love for Leta along their unpredictable journey to the discovery of CHOPS Syndrome:

Q: Tell me about Leta; she seems to have quite a big personality

Lainey Moseley: It blows me away that so much is going on inside that little body of hers. It is so hard to really know what her potential is because we think she is brilliant and understands what is going on all the time. Yet, Leta has cognitive impairment, is nonverbal, has small stature, and she is pretty medically challenged with lung disease and pulmonary hypertension. Having said that, she does have a big personality given all her disabilities, and she endlessly amuses us with her antics. Life with Leta is chaotic and far from normal — the highs and lows are so extreme — but she gives us so much love in return. I cannot imagine our life without her.

Q: When you describe your search for a medical diagnosis for Leta as a “medical odyssey,” what does that mean to you?

Lainey Moseley: Like everyone else, we really wanted to have a healthy child. We realized early on that Leta wasn’t hitting her milestones, and at one year old she was diagnosed with lung disease, but for 16 years no genetics doctors were able to give us a definitive genetics diagnosis. After many years, we gave up caring about a diagnosis; a label wasn’t going to alter the course of Leta’s life. But it was still unsettling not knowing how her disabilities were going to unfold. What was her lifespan going to be? Was the lung disease going to be a degenerative condition? We had no idea what her capacity was for learning or speaking. When you don’t have a diagnosis, you don’t know the end game or what to expect.

Q: How did you feel when Dr. Krantz told you that he had found this genetic glitch in Leta’s exome?

Lainey Moseley: When Dr. Krantz called and told us that he had identified her gene mutation and that he actually had found two other kids like Leta, it was beyond exciting. I was so curious what these two other little kids, Liam and Nadira, would look like. Leta is so unique. It was hard to imagine that there were two other people in the world just like her. But the discovery also became important for other reasons. On an emotional level, when I found out her dad and I were not carriers of the AFF4 gene mutation, I realized that Leta’s medical issues were not my fault. All those years, I carried the burden that maybe I had done something wrong in my pregnancy that caused Leta’s genetic condition. A diagnosis let me off the hook of blaming myself. There’s nothing that I could have done differently to prevent it. This was just a random act of nature. That was a big turning point for me.

Q: So far, two other families are known to have the same genetic mutations as Leta. Why is it important for you to have this new connection?

Lainey Moseley: It is important because we share a medical bond and now have a support group to compare notes about our kids, like what medicines are the doctors prescribing for their lung disease? What kind of communication devices do we each use? Does your child have the same hyperactive personality as mine? They are all so much alike, it is now almost like having triplets. I really am looking forward to getting to know Liam’s and Nadira’s families better. Having them in my life makes me feel so much less alone in my journey with Leta. Liam’s mom and I have become Facebook friends, and she was with me every step of the way praying for Leta when she was in the hospital last month on a ventilator.

Q: Overall, how has your experience been being part of Dr. Krantz’s research team?

Lainey Moseley: The whole team has been phenomenal and so wonderful. They have been really supportive by keeping us informed about the ongoing AFF4 research. The genetics team is organizing a lunch next month so that our families can finally get together as a group. We’ve already learned that the research into the condition that Leta, Liam, and Nadira share could be groundbreaking in genetics and possibly lead to understanding roots of other genetic mutations. So that’s pretty exciting when it’s your child who is on the ground floor of that breakthrough. We’ve always thought that Leta is a superstar, but now she is a trailblazer in genetic research, giving other kids the chance to be born healthy.

Editor’s Note: For more information on how CHOPS syndrome sheds light on key events in human biology, read the press release. Also, learn more about Leta by reading the blog http://savingleta.com/, written by her mom, Lainey.

Including noting the “science of vaccines is clear” in a Jewish Exponent article, The Children’s Hospital of Philadelphia physician and Vaccine Education Center Director Paul A. Offit, MD, spoke to a number of media outlets about the recent measles outbreaks and the vaccine worries the outbreaks have induced. Dr. Offit is one of the most outspoken vaccine advocates in the country and co-creator of the rotavirus vaccine Rotateq.

“I think it’s a shame that what we have to be seeing in this country right now, which is measles coming back now with more than 100 cases, that we have to … suffer our bad choices by watching children suffer diseases which are preventable,” said Dr. Offit on CNN’s Erin Burnett Out Front. “I mean it’s always the children that suffer,” he added.

Measles is a highly contagious viral disease that results in an itchy rash. Between January 1 and February 27, 2015, 170 cases of measles were diagnosed in the District of Columbia and 17 states across the U.S., according to the CDC.

And according to additional CDC data, until recently measles had been on the decline, with the disease declared eliminated in the U.S. in 2000. However, outbreaks in 2014 and 2015 show a marked rise in the incidence of the disease.

In a press briefing about the measles outbreaks, the CDC’s Anne Schuchat, MD, director of the National Center of Immunization and Respiratory Diseases, said the “majority of the adults and children that are reported to us for which we have information did not get vaccinated or don't know whether they have been vaccinated. This is not a problem with the measles vaccine not working. This is a problem of the measles vaccine not being used.”

Indeed, because measles is viral, there is no treatment for the disease, and the best protection is the measles, mumps, and rubella (MMR) vaccine. However, some parents have refused to give their children the MMR vaccine, fearing it could lead to autism.

The link between vaccines and autism dates to a retracted 1998 The Lancet paper by British physician Andrew Wakefield, MD. That now-debunked study started a series of vaccine safety concerns related to autism that were fueled by a well-organized anti-vaccine movement, vocal celebrities like Jenny McCarthy, and poorly researched media reports. Each concern put forth by the anti-vaccine movement — whether MMR vaccine carried risks, to mercury in vaccines, or whether children received too many vaccines — was studied scientifically and disproven. Nonetheless, the damage was done.

Two fundamentalist Christian churches — Faith Tabernacle Congregation and First Century Gospel Church — were at the heart of the outbreak. Children had not been vaccinated, and when they became ill, their parents prayed instead of taking them to the hospital to receive the intravenous fluids or oxygen that could have saved the lives of those with the worst cases.

A recent Journal of Clinical Endicronology and Metabolismstudy shows body mass index (BMI) during infancy may help to predict if a child will be obese by age four. In work focused on the infant BMI-childhood obesity relationship in a cohort with a majority of African-American children, researchers from The Children’s Hospital of Philadelphia say a better understanding of infant growth patterns may lead to more effective early efforts at obesity prevention.

“Given the public health importance of obesity-related medical problems, we investigated whether BMI in infants could be used as a tool to identify children at increased risk of future obesity, in order to develop better prevention strategies,” said the study’s leader, Shana E. McCormack, MD, a pediatric endocrinologist at CHOP. “We also analyzed ancestry-based differences in growth patterns, and found differences that were apparent at as early as nine months of age were ultimately related to childhood obesity risk.”

As a measure that includes both weight and height, BMI is an approximation of body fat content. BMI increases after birth, reaching its peak in infancy, usually between eight and nine months of age.

The current study analyzed the electronic health records of 2,114 healthy Philadelphia-area infants, as part of a larger study conducted by the Center for Applied Genomics. Sixty-one percent of the children in the study cohort were African-American, a population that, according to national estimates, has high rates of obesity and diabetes in adulthood. Investigators hope that more reliable, early identification of all infants at increased risk for obesity will offer a unique opportunity to develop and implement targeted interventions.

The research team identified significantly different growth trajectories between African-American infants and white infants. Peak infant BMI occurred around 12 days earlier in African-American children, and was about 3 percent higher in magnitude than others in the study, who were primarily of European ancestry. Overall, African-American infants appeared to have more than twice the risk of obesity at age four compared to infants of primarily European ancestry.

However, the study team performed statistical analyses to distinguish the effects of ancestry and infancy BMI, while also accounting for other factors such as birth weight and socioeconomic status. Their conclusion was that infancy BMI played a more important role than ancestry in determining the risk of childhood obesity. In addition, socioeconomic factors, inferred from geographic and insurance data, played a role in infancy BMI. Higher rates of poverty, for instance, were associated with higher and earlier peak BMI.

Sani M. Roy MD, the study’s first author, noted the current study provides rich longitudinal data, including drawing on the many measurements that are made routinely during infancy and early childhood at well-child check-ups. It is one of the largest studies to date using longitudinal data in such a diverse population.

The actual causes of these differences in infancy BMI and risk of childhood obesity in African-Americans remain subjects for further research. One co-author, Babette S. Zemel, PhD, the director of the Nutrition and Growth Laboratory at CHOP, is leading a prospective study of African-American infants and families, investigating factors such as hormone levels, variations in intestinal bacteria, and feeding practices such as breastfeeding and formula feeding on growth and excess weight gain.

In children under age two, there is currently no consensus definition of obesity, said Dr. McCormack.

“In the absence of an accepted, valid definition of obesity in infancy, we struggle both as researchers and clinicians with how to best individualize recommendations for infants to prevent childhood obesity,” she added. “Our findings suggest that infant BMI pattern could be one additional tool. In addition, infant BMI may be an early metric to use in evaluating the impact of public policy interventions.

Severe pediatric sepsis is a formidable challenge for critical care specialists who unfortunately see children in pediatric intensive care units (PICUs) die from body-wide inflammation and subsequent organ damage that can occur when the immune system responds to infection. Until recently, researchers had not defined the true scope of severe pediatric sepsis worldwide.

Previous studies that attempted to look at the epidemiology of severe pediatric sepsis used administrative databases based on billing codes or were conducted at single centers. Dr. Fitzgerald and Dr. Weiss received an overwhelmingly positive response three years ago when they approached fellow members of the broad, international Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI) with their study design. They were eager to get a clearer and bigger picture of severe sepsis that they could rely on to provide baseline data for future interventional trials to improve survival for their patients.

“When we look at our own ICUs, while mortality has gone down, it is still a lot higher than what was being reported in these administrative studies,” said Dr. Fitzgerald, who also is an assistant professor at the Perelman School of Medicine at the University of Pennsylvania. “So, in our minds, we were trying to resolve that discrepancy. We wanted to see what other ICUs’ experiences were in terms of how much sepsis they had and what their mortality rates were. We thought it was a bigger problem than maybe was being appreciated based on those administrative studies.”

They conducted SPROUT in 128 sites from 26 countries and screened a total of 6,925 patients on five days throughout 2013 and 2014. Using consensus criteria for severe pediatric sepsis, the researchers identified 569 patients. Their average age was 3, and 25 percent did not survive, which was much higher than previous administrative studies that reported mortality rates in the 5 percent to 8 percent range.

“Another key feature was the burden of pediatric severe sepsis in ICUs worldwide,” said Dr. Weiss, who also is an assistant professor of Anesthesiology, Critical Care, and Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “We found an overall prevalence of 8.2 percent, which means that your average PICU is treating at least one child with severe sepsis at any one time. So it is an incredibly common cause of pediatric critical illness, and it highlights the ongoing problem of severe sepsis.”

With these new estimates, researchers now have a better idea of how many centers and patients would be available for future interventional studies of severe pediatric sepsis. SPROUT also provided data on other outcomes measures such as multiorgan dysfunction syndrome, ventilator days, and the need for vasoactive medications. This information will facilitate better study planning, Dr. Fitzgerald said.

“SPROUT highlights the incredible collaborative spirit of the pediatric critical care community worldwide and the willingness and desire of investigators, even from relatively small sites from across the world, to participate in efforts to better understand the burden of the disease that we’re caring for and to ultimately put into place efforts to improve the care that we provide,” Dr. Weiss said.

The SPROUT study investigators’ work is especially noteworthy because they received no financial compensation for their participation. Dr. Weiss and Dr. Fitzgerald gratefully acknowledged the funding and divisional support from CHOP’s Robert Berg, MD, division chief Critical Care Medicine, and Vinay Nadkarni, MD, endowed chair of Critical Care Medicine. CHOP’s Center for Pediatric Clinical Effectiveness also provided grant support to help develop the research database to launch the study. They also thanked Jenny Bush, clinical research study coordinator.

The senior author on the study, Neal Thomas, MD, is a leader in the PALISI network and an established clinical scientist in pediatric critical care at Hershey-Penn State. He has been supported by the CHOP Division of Critical Care Medicine to mentor junior faculty at CHOP, including Drs. Weiss and Fitzgerald.

CVID affects one in 25,000 to one in 50,000 people worldwide, and they may start experiencing signs and symptoms of the disorder anytime between childhood and adulthood. Researchers suspect that mutations in the genes associated with CVID result in a shortage of antibodies that leaves the body vulnerable to infections from bacteria and viruses. Recurrent respiratory infections can lead to chronic lung disease, and patients also may have joint inflammation, stomach and bowel disorders, and a higher risk of cancers.

The study team performed an association analysis that focused on immune-related genes in a cohort of 360 CVID patients and 21,610 healthy controls. They compared regions of the genome using a genotyping chip specialized to search for gene variants previously implicated in autoimmune and inflammatory diseases.

The researchers found 11 single nucleotide polymorphisms (SNPs) associated with CVID on the 16p11.2 locus of chromosome 16. SNPs are changes in a single DNA building block (A,T, C, or G), compared to the more typical sequence in a certain stretch of DNA. Of particular interest, the study team found variants in the gene ITGAM, which carries codes for an integrin protein that regulates cellular contact and adhesion.

“This association is of high biological relevance because ITGAM plays an important role in normal immune responses,” said Hakon Hakonarson, MD, PhD, director of the CAG, who led the study team. “Other researchers have shown that mice in which this gene has been knocked out have immune deficiencies.”

The new findings may promote better understanding of ITGAM’s functional role and eventually lead to targeted therapies for patients with CVID. Dr. Hakonarson added that the research may have broader implications for other patients who do not have these novel gene variants because the integrin protein affects many important pathways in immune function.

“This discovery fits well with the ‘precision medicine’ concept that is currently in its infancy but represents the future of genomic medicine,” said Dr. Hakonarson, who is also on the faculty of Perelman School of Medicine at the University of Pennsylvania.

Clinicians at The Children’s Hospital of Philadelphia care for patients with complex medical and surgical conditions, and many rely on sophisticated technology long after they return home. The initial transition from hospital to home can be a daunting time for parents, as they take charge of operating this equipment, such as responding to ventilator alarms or keeping gastrostomy tubes in place.

A pilot quality improvement project underway at CHOP aims to reduce the emotional and operational stress on these families by conducting virtual visits via video chat on mobile devices a few days after children are discharged. Lead investigator John Chuo, MD, MS, hopes that by describing and characterizing the kind of issues that parents are facing, the implementation team will be able to better understand how telemedicine could be of value to augment the standard of care and perhaps avoid urgent care or emergency room visits and readmissions.

“The providing staff at CHOP are excellent at educating parents before discharge, but it can be overwhelming for parents who overnight become the sole caretakers for their child,” said Dr. Chuo, who is an attending neonatologist and medical director of telemedicine at CHOP. “It is a vulnerable time, for the patient and their quality of care, so we want to use telemedicine to help them make the transition.”

The research project methodology centers on a quality improvement framework, which gives investigators the flexibility to problem-solve using “plan-do-study act” cycles based on the data learned during the remote check-ins. They already have engaged several CHOP teams such as the Chronic Lung Disease Program in the Division of Neonatology, the Division of Plastic and Reconstructive Surgery, General Surgery, Home Care, and Compass Care, which seeks to improve the health of the most medically complex patients.

Those teams each have dedicated clinicians to participate in the project. Together with the telemedicine team, they will follow specific “swimlane” workflows that include identifying families willing to take part in the study, setting up parents’ mobile phones or tablets, and making appointments for the video chats before discharge. When it is time for the appointment, the clinicians will use a hosted service to connect with the families by video call and interview the parents based on a checklist of questions that are pertinent to their child’s care.

These are typical questions that would be asked via a telephone call with one addition — now, the clinicians can ask “show me” questions that may uncover issues not discoverable before with voice only calls. The items will help to reinforce education and resolve parents’ questions, focusing specifically on use of equipment and supplies, certain medical and surgical screening, compliance with medications and appointments, and unanticipated events and complications.

For example, the clinician will ask, “Are you having any problems administering the medication?” and then follow up with, “Please show me how to draw up one of your medications.” Having parents demonstrate their technique using the syringe could help to avoid medication errors. Another example is asking parents to show the clinician the child’s feeding tube site. Most mobile devices’ cameras have high enough resolution, Dr. Chuo pointed out, that the clinician potentially could see the condition of the insertion site.

Afterward, the clinician will document the virtual patient encounter in a database and communicate information to other providers, as they normally would do. Over a 12-month period, the researchers will track call rates, home visit rate, emergency room referrals, readmission rates, patient and provider satisfaction, and the number of equipment and patient issues that were identified and resolved.

In the end, Dr. Chuo expects to identify clinical scenarios where the use of video calls would have greatest value and learn how to better implement telemedicine in those situations as a way to optimize care coordination and overcome geographic barriers to access. Some families do not have an easy means of seeing a specialist should something unexpected arise, and most go to the emergency room when problems escalate.

“We are dedicated to providing children access to the right care at the right time,” Dr. Chuo said. “From a healthcare community standpoint, better and quicker access can reduce healthcare costs. The use of telemedicine has avoided patient transports by ambulance, thereby from a quality improvement perspective, it reduces travel time, which is non-value added work.”

Dr. Chuo, who also is an assistant professor of Clinical Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, is appreciative that CHOP already has in place the clinical infrastructure and support for patient care to make this project possible. He gave kudos to CHOP’s Information Technology and Telemedicine groups for facilitating the study team’s easy access to a simple-to-use, reliable communications platform. Dr. Chuo also expressed special thanks to Verizon for their ongoing financial support of telemedicine research initiatives at CHOP.

During pregnancy, a series of intricate processes takes place for the heart to form correctly. Cells develop, proliferate, migrate, and die frequently, as the heart tissue transforms from a primary heart tube to four cardiac chambers. Scientists suspect that if there is a genetic mishap, those steps may not occur at the right time or place, resulting in congenital heart defects (CHDs).

One in 125 babies in the U.S. is not born with a perfect heart. CHDs are the most common major birth defects, and they range from simple to complex. For example, a heart defect called ventricular septal defect (VSD) involves an opening in the dividing wall between the two lower chambers of the heart. The hole allows an extra volume of blood to be pumped into the lungs, creating increased pressure, stress, and congestion.

Researchers at The Children’s Hospital of Philadelphia are searching for genes that could be linked to the presence of heart defects, and they recently reported on mutations in the gene NTRK3 that may be involved in the development of VSDs. NTRK3 regulates cell survival and encodes a protein called neurotrophic tyrosine kinase receptor C (TrkC).

“Finding the potential variations that are involved in heart defects in children is like finding a needle in a haystack, but you’re looking at a field of hundreds of haystacks,” said Petra Werner, DVM, PhD, a senior research associate in the laboratory of Elizabeth Goldmuntz, MD, professor of pediatrics in the Division of Cardiology at CHOP. “We picked NTRK3 as a candidate gene because deletion of this gene in mice will result in heart defects, and we had identified a patient with a VSD that had a large deletion encompassing NTRK3.”

In an article published in the December issue of Human Mutation, Dr. Werner and colleagues described how they screened 467 patients with related heart defects for NTRK3 mutations. They identified four of those patients with VSDs who had a missense mutation, which means an amino acid substitution occurred in the TrkC protein made by the gene that may modify how it works.

Next, the study team conducted experiments to see if the mutated TrkC lost any function. As a receptor, TrkC sits on cells’ membranes and waits for a signal from its ligand, a protein called neurotrophin-3 (NT-3). The results showed that one of the mutations significantly reduced TrkC’s ability to respond to the ligand, and subsequently TrkC failed to activate essential downstream signaling pathways.

In addition, the investigators found that cells expressing mutant TrkC showed altered cell growth. Usually, when NT-3 is present and binds to TrkC, it is a survival signal for the cell to differentiate and migrate. When the NT-3 ligand is absent, the cell begins to die, a process known as apoptosis. The experiments showed that cells with some of the mutant TrkC kept growing, even when they lacked NT-3.

Dr. Werner and her colleagues hypothesize that if TrkC’s function is impaired and allows the wrong heart cells to differentiate and migrate, then flaws could occur during the rapid remodeling of embryonic heart development.

“They may end up in the wrong location in the heart and be missed in other locations, resulting in malformations or holes,” Dr. Werner said. “But much more research must be done before we fully understand all of TrkC’s functions.”

In an ideal world, the very best grant proposals that are the most likely to advance scientific discovery would win financial support from the National Institutes of Health (NIH). But the reality is that science is not immune to human bias. Race, ethnicity, gender, career stage, institution of origin, and other factors can accumulate as competing biases that may influence — consciously or unconsciously — how peer reviewers score submissions.

While this is no surprise to the research community, investigators may be taken aback by the results of a simulation study published in the journal Research Policy by T. Eugene Day, DSc, of the Office of Safety and Medical Operations at The Children’s Hospital of Philadelphia. He assessed how much bias is needed before grant funding decisions are swayed.

In his role as principal health systems specialist, Day uses simulation tools to examine clinical delivery systems and make predictions about which potential quality or safety interventions are most likely to have a positive change at CHOP. For example, he was the principal investigator for a recently published study that demonstrated how his team used simulation to test plans to improve scheduling of elective procedures in pediatric cardiac care.

During his free time, Dr. Day designed a thought experiment based on a simulation model of a simplified grant review process. He formulated the idea after a social media conversation with colleagues about how slight advantages could play a big role in determining who is lucky enough to submit a successful grant application when federal research dollars are scarce.

Dr. Day created two fictional classes of investigators for the simulation — preferred and non-preferred — and he assigned each class 1,000 grant applications that had been given intrinsic quality ratings. He ensured that the quality of the grant applications from each group was statistically identical. Then, in order to mimic the peer review process, he generated three reviewers who were imperfect at determining the intrinsic quality of the grants.

“Just like in the real world, no three reviewers on a NIH grant ever agree on exactly how good it is,” Dr. Day said. “The same was true in the simulation. I based the distribution of that randomness from my own grant score history.”

After validating the model, Dr. Day conducted a sensitivity analysis. He introduced small biases in one or all three reviewers against the non-preferred investigators and then increased the level of bias until he found statistically significant differences in the scores and in the actual awards, despite the fact that the quality of the grants was the same.

“What I found was that it takes an alarmingly small bias to make a significant difference,” Dr. Day said. “With only about 2 percent of the score being bias, we saw statistically significant differences in the scores of grants. That did not translate to the number of funded awards at that level. But with 3 percent, we saw statistically significant differences in the actual funds distributed. Very small biases can make these rather dramatic impacts on who gets funded.”

Another provocative aspect that his simulation revealed is that while the more privileged investigators received funding and the underprivileged investigators were left behind, the average quality of the funded grants was lower than it would have been without bias.

“So not only do these biases influence who gets funded, but they may degrade the overall quality of science,” Dr. Day said.

In addition, Dr. Day pointed out that bias can be difficult to detect because it is overshadowed by the random variation in how good reviewers are at determining the quality of the grants. In other words, the signal is a lot smaller than the noise. A first step to honing in on bias would be to promote more transparency in the grant review process, Dr. Day said, specifically by publishing the variation in individual reviewers’ scores.

“The first thing that we need to do is understand how big the variation is, and then next we need to work on narrowing it,” Dr. Day said. “That will allow us to identify real-world bias, which might then be addressed.”

Several efforts already are underway to maximize the fairness in NIH peer review. Last spring, Director of the NIH’s Center for Scientific Review (CSR) Richard Nakamura, PhD, announced an initiative to begin combing through grant proposals to remove identity cues and then testing to see if anonymization has any effect on funding disparities. The CSR, which is the gateway for NIH grant applications, also launched a challenge to produce the best ideas to detect possible bias in peer review and named the winners in September.

It is crucial for the NIH to seek solutions to overcome bias, Dr. Day said, because challenges in securing grant funding that are unrelated to submissions’ merit can have long-term consequences for investigators who are striving to pursue promising biomedical research.

“If a bias prevents you from getting that first grant, then maybe you don’t have the preliminary data that you need for the next grant,” Dr. Day noted. “Maybe you don’t have the funding to continue your laboratory, and you exit science.”

The Children’s Hospital of Philadelphia Research Institute has a robust training program for researchers at multiple levels, including CHOP-based graduate students, postdoctoral fellows and physician fellows. During CHOP Research’s recent Poster Day event, the Institute took time to recognize notable advanced research trainees without whom the groundbreaking medical research conducted every day at CHOP would be impossible.

The 2015 Distinguished Research Trainee Awards, chosen by the Research Trainee Advisory Committee, went to graduate student Drew Comrie, PhD; physician fellow Elizabeth Bhoj, MD; and postdoctoral fellows Dong Li, PhD, and Daniela Eletto, PhD, who tied for the honor. The winners’ expertise — in immunology, genetics, and molecular biology — spans the research spectrum.

The CHOP Distinguished Research Trainee Awards provide institution-wide recognition for exceptional CHOP Research trainees, and offer an opportunity for mentors to highlight the work of their researchers-in-training. Each awardee is featured on the CHOP Research Office of Postdoctoral Affairs (OPA) Trainee Web Portal, recognized with an award certificate, and awarded a prize.

T Cell Mechanics

After receiving his BS in Microbiology and Immunology from the University of Rochester, Drew Comrie, PhD, went on to receive his PhD from the University of Pennsylvania in the fall of 2014. From 2009 until his graduation from Penn, Dr. Comrie worked in the laboratory of Janis K. Burkhardt, PhD.

“Drew is one of the most talented and intellectually independent students I have ever had in my lab, and one of the very best that I have encountered in any lab at CHOP, Penn, or the University of Chicago,” said Dr. Burkhardt.

Dr. Comrie is the first author of tworecentJournal of Cell Biologypapers (published back-to-back) — both of which Dr. Burkhardt led — on the mechanics of T cell activity. The work, which “reveal[s] that the actin cytoskeleton on both sides of the [immunological synapse] promotes the full activation of LFA-1 in order to enhance T cell priming,” was recently profiled in a Journal of Cell Biology “In Focus” article. In addition, Dr. Comrie’s research was integral to an R01 Dr. Burkhardt received from the National Institute of General Medical Sciences.

Since receiving his doctorate, Dr. Comrie has gone on to a postdoctoral position in the lab of Michael J. Lenardo, MD, in the National Institute of Allergy and Infectious Disease’s Laboratory of Immunology.

“I am excited that he will take his talent for basic science and apply it to understanding rare and devastating immunological diseases,” noted Dr. Burkhardt. “This is just the sort of scientist that CHOP is poised to train.”

Both Drs. Bhoj and Li were mentored by Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics (CAG). Dr. Bhoj’s work has been focused on identifying genes associated with craniofacial development, while Dr. Li has, in part, acted as a project manager for several collaborative CAG projects, helping to identify multiple new disease-causing genetic variants.

Dr. Bhoj, said Dr. Hakonarson, “stands out in my mind as outstanding in her potential for and commitment to a highly successful academic research career. I am certain that in the years to come she will continue to accelerate her trajectory of scientific success in advancing the understanding and treatment of genetic disease.” And Dr. Li, Dr. Hakonarson noted, “was a top-tier postdoc in terms of his research skills, learning capacity, solution finding, and efficiency, and he is extremely hard working and dedicated to his projects.”

“It is exciting to learn about the underlying genetic/molecular mechanisms of diseases and the implications of these insights for human physiology,” said Dr. Li. “So thanks to CHOP, and especially Dr. Hakonarson, for the continuous support and all the time he put into my research. I’m very grateful and honored to be recognized.”

Exploring the Endoplasmic Reticulum Stress Response

And last but certainly not least there is Daniela Eletto, PhD. Originally from Italy, Dr. Eletto received both her PharmD and PhD from the University of Salerno, and first came to CHOP in 2010 while still working toward her doctorate. Since 2012 she has been a postdoctoral fellow in the laboratory of Yair Argon, PhD, who called Dr. Eletto “very insightful, motivated, and a fast learner.”

“Since joining the lab as a postdoc, these traits have been more evident, but I have also been impressed by Daniela’s desire to engage in intellectually challenging problems,” Dr. Argon added.

Much of Dr. Eletto’s work has been centered on better understanding the molecular underpinnings of cell death. In particular, she has been working with Dr. Argon on research on the endoplasmic reticulum’s stress response, and last year Dr. Eletto was the first author of a Molecular Cell paper that shed light on how cells deal with stress.

When stress is placed on the endoplasmic reticulum (ER), cells’ ability to synthesize, fold, and mature proteins can be impaired. ER stress has been associated with a range of conditions, including amyotrophic lateral sclerosis (also known as Lou Gehrig’s disease), cancer, and heart disease. Cells’ response to ER stress is the unfolded protein response (UPR), in which sensors are activated in an attempt to return the cell to homeostasis or, failing that, to induce apoptosis. In the Molecular Cell study, the study team learned new things about how UPR sensors are regulated.

“As Daniela continues to develop and mature as a scientist, she has made a nice transition from focusing on ‘how to’ conduct experiments to ‘which’ experimental approaches are best suited for the problem at hand,” added Dr. Argon.

To read more about each of this year’s awardees, and to learn more about training and education at CHOP Research, see the CHOP Research site.

Two undergraduate engineers from the Center for Injury Research and Prevention (CIRP) were recently honored during CHOP Research Poster Day. Held February 25, 2015 Poster Day was the 25th anniversary of the event, and 40 researchers’ work was selected by panel of faculty judges to receive awards. Among a collection of hematologists, oncologists, and neonatologists, the research Richard Hanna and Todd Hullfish presented — focused on child restraint systems and side air bags, respectively — stood apart.

Currently in his final year at Drexel University, Richard Hanna has been working toward a Master of Science in Biomedical Engineering. Since coming to CIRP in June 2014 through CIRP’s National Science Foundation (NSF)-funded Injury Science Research Experiences for Undergraduates program, he has assisted with data analysis and co-authored a paper to be presented at the SAE World Congress and Exhibition in April.

Todd Hullfish, meanwhile, has been studying toward a Bachelor of Science in Mechanical Engineering and has been at CIRP since September 2013; prior to coming to CHOP, he worked with insulin pumps at Animas, a division of Johnson & Johnson. At CIRP Hullfish has analyzed motor vehicle crashes, worked on an IV monitoring system, and developed computer models of crash scenarios. Hullfish came to CHOP through Drexel University’s Co-op program, in which Drexel students gain experience in their future fields at employers across the United States and internationally.

Richard Hanna’s award-winning project was focused on using the Microsoft Kinect for Windows motion-sensing device. Perhaps best known as an Xbox peripheral (allowing users to play games with gestures rather than a controller), Hanna used the device in a novel way: to create three-dimensional digital models of 48 child restraint systems (CRS) representing close to 300 child seats in the US market as of March 2015.

According to a 2013 CIRP report on child passenger safety, motor vehicle crashes remain the leading cause of death for children older than 4 years and resulted in 952 fatalities in 2010 for children age 15 and younger. Although the number of children restrained in CRS has risen due to awareness and legislation, unintentional misuse of these restraints remains an issue; a 2004 NHTSA survey found that 72.6 percent of child restraints observed in parking areas throughout the United States had at least one “critical” misuse.

With this study, Hanna and Dr. Belwadi sought to make it easier for vehicle manufacturers to evaluate CRS-to-vehicle fit early on in the design phase, rather than an after-thought process once the CRS has been purchased. Currently, there is no standard method of quantifying CRS geometry and volume, and the Kinect presents a simple, economic alternative to methods currently used by manufacturers.

Hanna’s work was previously recognized last summer at the 9th annual CIRP student research day. And Dr. Belwadi recently wrote about CIRP’s use of the Kinect in a post on the CIRP blog, noting “results from this research can ultimately help to improve testing conditions for vehicle and restraint safety devices.”

“As we begin to utilize “unconventional” data collection tools such as the Kinect sensor for scanning, tracking, and quantifying shapes of safety devices and actual people, we are seeing that the technology is very promising for several applications beyond the gaming industry,” wrote Dr. Belwadi.

“It’s a great honor to be recognized alongside of the remarkable people working at CHOP who lead research in incredible and ground breaking areas,” said Hanna. “It was quite a humbling experience to witness the spread of projects and the passion all contestants showed for their work. I think that engineering as a discipline has come a long way in making a presence within the field of biology and medical care, and I look forward to what the future has in store.”

Todd Hullfish’s project, meanwhile, explores the effectiveness of side air bags and their interaction with pediatric passengers, a little studied topic. While various types of side air bags have become standard in many vehicles, the degree to which they protect passengers is up for debate. To get a better sense of how side air bags affect children seated next to them, Hullfish used Finite Element Modeling (FEM) to model computer simulations of side impact crashes with accurate anthropometric test devices (ATD), or crash test dummies.

What, then, is FEM? Last summer Hullfish wrote a post for CIRP’s blog about FEM, which he defined as “a method of computation that represents complex geometry with simple shapes, such as triangles and squares in what is referred to as a ‘mesh’.”

“By breaking down complex shapes into much smaller, more manageable components, we’re able to analyze systems that would otherwise be too difficult to solve by other means,” Hullfish wrote.

The researchers use of a computational model allowed them to examine in detail side air bags’ deployment and effectiveness. The researchers next plan on testing pediatric models, in a variety of CRS designs. Their work could help vehicle manufacturers and CRS companies design more effective systems for child passengers.

“Being recognized for my work at CHOP’s Research Poster Day has been wonderful and, admittedly, a bit surprising,” said Hullfish. “It has been humbling to have my research counted among such stellar work. As an engineer working alongside healthcare professionals I am constantly encouraged by the level of interdisciplinary respect present in this community and hope to see that respect continue to foster more incredible research.”

Going forward, Hanna has said he is interested in working in the medical device or automotive biomechanics industries, while Hullfish — who doesn’t graduate from Drexel until 2016 — is considering graduate school.

“I’m extremely proud of Rich and Todd’s accomplishments. For engineers to be recognized among the world-class clinicians at CHOP is truly remarkable,” said Dr. Belwadi.

Dr. Belwadi’s current projects were funded and supported by the Center for Child Injury Prevention Studies (CChIPS), an NSF-funded Industry/University Cooperative Research Center that focuses exclusively on improving the safety of children and adolescents. CChIPS provides a very unique opportunity and funding mechanism to pursue cutting edge research that is applicable directly to the automotive industry, he noted

Started as a pilot program in 2012, CRISSP pairs promising undergraduate scientists with leading CHOP researchers for a 10-week program, from June to August. In addition to offering undergraduates valuable laboratory and clinical research experience, the program also supports their professional development with networking lunches and other events, and CRISSP interns conduct informational interviews to learn more about graduate and medical school. They are given the opportunity to shadow clinicians, and are trained in laboratory safety, animal use, and human subjects protections.

“It has been inspirational to work with CRISSP faculty and students over the past several years,” said Ian Krantz, MD, the program’s principal investigator. “I am amazed at the maturity and drive of the students who we have had the pleasure to host in my lab and the quality of the overall program in providing a unique and valuable research experience to these undergraduates. The support of the NICHD through the R25 grant will allow CRISSP to formalize and extend its efforts in providing one of the most exceptional undergraduate summer research experiences in the country.”

Since its inception, the program has been a runaway success. CRISSP’s applicant pool has nearly doubled since 2012, with 2015 applications coming from more than 164 schools for 25 spots. Moreover, administrators have seen a rise in the overall strength of applicants, making the selection process that much more difficult.

“It is has been a true pleasure for me to be part of CRISSP from the very beginning and to see firsthand the incredible degree of commitment and enthusiasm on the part of the CHOP administrators in charge of it and the unwavering support of the faculty,” said orthopedic expert Maurizio Pacifici, PhD, who in 2014 mentored CCP student Adebayo Bello.

The NICHD grant will allow CRISSP’s managers to increase their efforts to diversify the program, add faculty and student mentoring services, offer Responsible Conduct of Research training, and add a high school component to the program. In particular, the funding will support a half-day, “Research in Action” event for Philadelphia-area high school students. The annual event will expose students — starting with those from Philadelphia’s Science Leadership Academy — to the wide array of research performed at CHOP Research every day.

Dr. Williams and her team will also use the NICHD funding to develop a mentor training program for CRISSP-associated faculty and staff. Dr. Durbin, who has mentored many junior faculty members and physician fellows over the years, and who has studied research mentoring, will lead the CRISSP Research Mentor Training Program.

Moreover, the NICHD grant will fund the development of a mentorship training program for CRISSP students, to help them learn how to be an ideal mentee as well as how to mentor others. And it will help develop a workforce “pipeline” that encourages talented high school students, particularly under-represented minority students, to pursue careers in biomedical science.

“The CRISSP students have turned out to be what we had hoped for, a group of amazingly motivated, hard working, scientifically curious and diligent young people,” said Dr. Pacifici. “It has been fun to get to know them, learn about their life trajectories and plans, and help them implement their dreams in the future. It would be indeed fantastic if the CHOP Research Institute, and the students’ experience here, were to make a real difference in their life.”

“We were so pleased to receive this grant from the NICHD,” said Dr. Williams. “Its support will be integral to growing CRISSP, and inspiring the next generation of biomedical researchers to pursue rewarding careers in science.”